Manufacture of therapeutic substances



2,876,225 MANUFACTURE OF THERAPEUTIC SUBSTANCES George H. Donnison, South Wellfield, Whitley Bay,

Northumberland, England, assignor to Abbott Laboratories, Chicago, 11]., a corporation of Illinois No Drawing. Application June 13, 1956 Serial No. 591,024

Claims priority, application Great Britain June 15,1955

14 Clain1s. (Cl. 260-257) This invention relatesto the manufacture of useful chemical substances and more particularly to the manufacture of therapeutically usefulthiobarbituric acids.

f Thioharbituric acids having the general formula:

C=S C-N/ g H wherein Rand R are hydrogen or saturated or unsaturated alkyl, cycloalkyl, cycloalkylene, or aryl groups, and S is sulfur, and the salts thereof, are known to have useful therapeutic properties. 1 These compounds, wherein R and R have 2 to 6 carbon atoms, are particularly effective-a hypnotics, sedatives, and anesthetics. One important use of the thiobarbituric compounds of the latter type is for inducing surgical anesthesia ofrelatively short duration, and for such use dilute aqueous solutions are injected parenterally in relatively large amounts. It should therefore be appreciated that the purityof these compounds is very important. I

Heretofore, the method most generally used for preparing these thiobarbituric acid compounds has 'been to condense hone molecular equivalent of a di-substituted malonic ester with one or more molecular'equivalents of time or thiourea in the presence of. sodium ethylate. The solvent generally used for the foregoing reaction is an alcohol or a hydrocarbon solvent. A reaction temperatureof from about 99 C. to 120 C. is maintained for about .18 hours. The barbituric acid formed is isolated from the reaction mixture in an impure form by precipitating the said acid from. an aqueous solution thereof by the addition of a mineral acid... Further purification must be effected by dissolving the barbituric acid in alkali and reprecipitating. by the addition of acid.

c 'It is a further object-of the present invention to provide,an;,,improvedprocess of producing more economically a thiobar'bituric acid compound having the required hielit g purityjILis" stillanother object of the preseritinvention to proyide animproved process of producing thiobarbituric ac1ds,,wher einincreased yields of ahighly purified prodnet are obtained in a moreeconomical manner.

:Otherpbjectsof the .presentiinvention will be apparent ftomfthe detaileddescription and claims to follow.

-Accordingto the present invention, the herein'disclosed '2 new process of manufacturing barbituric acids isbroadly characterized by condensing a di-substituted malonic ester having the general formula:

0 R/ COOR" wherein R and R are hydrogen or saturated or unsatu rated alkyl, cycloalkyl, cycloalkylene, or aryl groups,'and

R" is a lower alkyl group with an active metallo deriva tive of a carbamide selected from the group consisting of urea, N-lower alkyl urea, thiourea, and N-lower alkyl thiourea, such as is formed when the said urea or thiourea is reacted with alkali or alkaline earth metal alcoholate, sodium hydride or the like alkali or alkaline earth metallating compound, said metallo derivative being formed in the'pres'enc'e "of the saidmalonic ester or apart therefrom aud wherein the said condensation reaction is carried out at such temperatures and pressure as to preclude decomposition, other than a negligible decomposition, of the thiobarbituric" acid compounds formed. By carrying out the reaction at atemperature' and under conditions which preclude decomposition taking place during the condensation reaction, a more highly purified product is obtained directly and the subsequent steps of preparing the pure acid and/or a water soluble salt 'thereof are greatly simplified, since several of the time consuming purification steps heretofore considered essential are eliminated. j f

The condensation reaction between the iii-substituted malonic ester compound and the urea or thiourea compound is preferably carried out at atmospheric pressure in which case the temperature of the reaction should not exceed about 60 C. Experiments carried out have shown that in the condensation reactions with a thiourea compound and a di-substituted malonic ester to form the desired thiobarbituric acid, the condensation reaction pro-- ceeds very effectively when the reaction is carried out at a temperature between about 551 C. and 60 C., at atmospheric pressure and fora period of between about 12 to 24 hours. For best results in the. commercialpreparation of a thiobarbituric acid, however, such as S-ethyl- 5-(l-methylbutyl)-2-thiobarbituric acid, the temperature during the condensation reaction should. not exceed 55 C. and for a period of about 18 to 24 hours at atmospheric pressure. Very high purity 5-ethyl-5-(1-methyl butyl)-2-thiobarbituric acid is also produced when the herein disclosed condensation reaction is carried out at a temperature of about.35 C. 'for atmospheric pressure. v

. In order that the invention may be more clearly un-. derstood, the following examples are included by way of illustrating the process.

Example I Clean sodium metal (282 gms.) is gradually added to a volume of methanol in excess of the theoretical volt me required to dissolve the sodium in order to provide a solution of sodium methylate in methanol; A suit able volume of methanol has been found to be 2700 cc,

a period of hours at The solution obtained is cooled to 60 C. and the temperature of the solution maintained within the range of 55-60 C., while thiourea, which has been thoroughly dried, is added. The amount of thiourea added to the solution is in excess of the theoretical amount necessary to react with the malonicester so as to cause the reaction to go to completion. Experiments have shown that a suitable amount of thiourea to be added to the methylate solution is 408 'gms. f i 1 1 After the thiourea has dissolved, 900 gms. of diethyl ethyl-(l-methylbutyl) malonate ester are added to the reaction mixture. The. reaction mixture is very carefully kept,v at a temperaturewithinthe range .5.5.- 60.. C. for. .4. hours, at the end of whichperiod the condensation reaction is found to be complete, which can be empirically tested by: taking a. smallvsample of the reaction mixture. andpouring-itintotwo volumesof water. The absence. of any unreacted ester floating on thesurface isindicative of the completion of the reaction.

The reaction mixture is then cooled to 20 C. and poured into /2 liters of water. As there is an excess of sodium methylate present in the reaction mixture, it is desirable to cool the reaction mixture. at this stage, since, under-the. alkaline. conditions, hydrolysis of thesynthesized; crude. sodium 5-ethyl-.5.-(1methylbutyl)-2-thiobarr bituratewould rapidlyoccur if the-temperature were too.

Accordingly, inthe. process described it is essentialto, precipitate thebarbituricg. acid as. quicklyv as, possible, sincejhe yield; would dropby asmuchas- 3%;iu24 hours. under the alkaline... conditions, employedv The. aqueous mixture. is treated as'quickly as. possible it activated rbonand filtered through a. suitable filter. When the fil ra i n i c mp wa er s. p mped hrough. he filt nd added o e a h. un l h filtrate nol n e iv s precipitate wi h cetic aci Th acid. 5 hyl -.(.1 m t y1buty 2 :thio:

a b u acid, sp ec pi ete by. th care ul; a ition of.

acetic ci .0% techn calluntil e mixture i acid to m s he i ba i u ic a dv s. hen fil e ed 9 f, w d cll w h water nd the i illed W t o emo e sodium acetate, and dried in an air drier at 90? C.

T ayie .Q hiq e ri a id bta ed is em or 0.81 gm. of acid per gm. of diethyl ethylfll-methylbutyl) malonate employed, i. e., physical; yield of 81%, (93.7% of the theoreticai yield The melting point of the product wasfoundto be 1 56-157. C. (uncorrected); i

I Evolution of hydrogen sulfide during the precipitation ofthe acid, which was a source. of trouble with the usual known method of preparation, is virtually eliminated inthe present process. i

Example II A cool dry still is charged with 545 kg. of methanol a moisture content of 0.025% or below and the is evacuated and thoroughly purged with nitrogen. sodium is slowly added to the methauol and addi t i nal sodium added to maiutainf refluxing of the. methiuol uutil a total of 71.8 kg'. of sodium has been add (1 and completely dissolved in the methanol. The

methylate solution thus formed is cooled to 5 5f and l02.2, kg. of thiourea which has been thoroughly dried at 75 C. is then added to the methylate solution. To the latter metallated thiourea solution at a temperature of 55 C. is added 227 kgpof diethyl ethyl- (l -methylbutyl) malonate and the temperature during the latter condensation reaction is maintained at between about 50 and 55 C. for 24 hours. At no time during condensation is the temperature of the reaction allowed to exceed 55 C. When the condensation is, completed, the reaction mixture is cooled to 20 C. and diluted with 400 gallonsof cold water, and 5 kg. of activated carbon and 5kg. of filter aid are added and the mixture stirred. The reaction mixture is then filtered rapidly and water is passed through the filter and added to the reaction mixture until the. discharge from "the filter no longer forms} precipitate with acetic acid. The cle ar filtrate isf then precipitated by theaddition of acetic acid (80% technical) until the mass remains acidic an mus; "The prcgipitatedfacid is then separated from the liquid by dentriiugation until substantially free. of liquid. The centrifuged acid is then slurr ied with about 500 gallons of water and recentrifuged; The washed centrifuged acid then removed from the centrifuge and granulated thereafter dried: in a hot air drier at a temperature of C. The product, 5-ethyl-5-(l-methylbutyl)-2- thiobarbituric acid, has a melting. point of 15.6 157 C and forms a clear solution in cold alcohol when added in a concentration of 10% to the said alcohol. A yield of about 81% (physical yield) of the said acid is obtained.

In order to minimize occlusion of sodium acetate during the subsequent precipitation of the thiobarbituric acid, the excess methanol inthe condensation. reaction may be removed in Whole or in part by distillation'in vacuo during the condensation. reaction while maintaining the reaction temperature at between 55 and 60 C. The following example illustrates the foregoing modification.

Example III Into a SOD-gallon glassslined stillis. charged 1625 lbs. of methanol. The still is purged with nitrogen and ch r e w h. 1 -3. b of s di m. metal-at. at whi h is su ic cn to ma tain n ta rflfl a-wnd iq a e still isv maintained at reflux condition until allthe s diun has dissolved in they methanol. Thereafter, the-alcohol solution of sodium methylate is cooled to 60 C. and 225 lbs. of thoroughly dried thiourea is added while maintaining a nitrogen atmosphere within the still. The mixture is thoroughly agitated to dissolve the thiourea and thereafter 500 lbs. of dry diethyl ethyl-(l-methylbutyl) malonate is added. The condensation reaction mixture is held at a temperature of 55 C. for 9 hours at which time a vacuum is applied to distill oif methanol,

whilev maintaining the temperature at 55 C. Over a period of. 9 hours, approximately gallons ofmethanol are removed while maintaining the temperature at 55 C.

The viscous reaction mixture is then poured intotwo; 300-gallon stainless steeltanks, each containing about 150 gallons (U. S.) of 50% ice and water. The mixture.

is agitated until uniformly dispersed and thereafter. 7; gallons of'benzene. are added to each tank. After standing for about 15 minutes following agitation, the benzene layer is separated and discarded. The aqueous solution is mixed with 10 lbs. of activated carbon and 8 lbs. of a suitable filter aid. After agitation, the mixture is filtered through a Sparkler filter into a 750-.gallon glass-lined' vessel equippedf with an eflicient agitator. Thereafter, 80% acetic acid is slowly added to the filtered solution withiagiitation until a pHof between about 7.0. and7.$. ismaintained. The precipitate which forms is then ecu-J trifu gedjand the product. is washed and continuously..ceri}-. trifu ged firmware with water at. fulll'line fe. The centrifuged product is theri air dried at 9 100 C. for about tvvo days to y'iel'dlbs. off'S-e'thYLS.

r ada e; ai has; a res of 1:56EQ157 C.

Example, IV

In 450cc. of methanol is added 47 gms. of metal and the mixture allowed to completely react to form a methanol solution of sodium methoxide. The methanol solution of sodium methoxide is then cooled to 60 'C. and 68 gms.'of thiourea which has been thor oughly dried is added with stirring until a uniform solu-, tion'is formed. Thereafter, 157 gms. of diethyl any (l-methylbutyl) malonate'is added to the solutionfof thev amass" The productis air-dried at a temperature-of 95-100 C. for 48 hours to yield 133 gms. of -allyl-5-(1 methylbutyl)-2-thiobarbituric acid having a melting point of l32-13 3 C. and assaying at 99.5% pure.

Example V Sodium methylate (16.4 gms.), thiourea (12 gms.), and diethyl diethylmalonate (21 gms.) areadded to 25 ml. of ethylene diamine. The mixture is maintained at a temperature of 60 C. for 16 hours and after cooling is poured into 100 ml. of water. Acetic acid is added to precipitate the product, 5,5 -diethyl-Z-thiobarbituric acid, which after filtering, washingwith water, and drying at about 100 C. yields 9.2 gms. of the said product having a melting point of 173 C.

Parenteral solutions of the sodium salts of the above thiobarbituric acids prepared in the foregoing specific examples are particularly useful as anesthetics. The sodium salts of the said barbituric acids are readily prepared by treating the said barbituric acids with alkali metal hydroxides or other alkali metal compounds. For example, the sodium salt of 5-ethyl-5-(l-methylbutyl)-2-thiobarbituric acid is conveniently prepared by dissolving one molecular equivalent of 5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid in warm absolute alcohol. The alcohol solution of the thiobarbituric acid is then added to a solution of one molecular equivalent of sodium ethylate in absolute alcohol. Upon evaporation of the alcohol, the sodium salt of 5-ethyl-5-(l-methylbutyl)-2-thiobarbituric acid separates as a crystalline solid which is readily soluble in water. The latter salt is conveniently administered in the usual manner as a 2% or 5% aqueous solution which is adjusted to have a pH of about 11, in accordance with the standard practice.

In the manufacture of barbituric acids in accordance with the present invention, other polar solvents can be employed in addition to methanol. Thus, ethanol, isopropanol, and similar polar solvents can be substituted. In the preparation of the herein disclosed barbituric acids, however, it is preferable to employ methanol. Other nonvolatile solvents which can be used in the process of the present invention are ethylene diamine and dimethylformamide.

In preparing the metallo derivatives of urea and thiourea compounds, metallo compounds other than the alkali and alkaline earth metal alcoholate can be used in the reaction between urea or thiourea to form the metallo compound. Thus, sodium hydride, sodium cyanamide, and sodamide can be used in place of the sodium methoxide or sodium ethoxide.

It will also be understood that other lower alkyl malonic esters can be used in addition to the diethyl malonic esters used in the several specific examples. Thus, in some instances it will be desirable to use a dimethyl malonic ester and in other instances a dibutyl malonic ester, as those skilled in the art appreciate.

Although the present invention has been described with particular emphasis being given to the preparation of 5- ethyl-5-(l-rnethylbutyl)-2-thiobarbituric acid and the sodium salt thereof, it will be understood that the present process is applicable to the preparation of all thiobarbituric acids and salts thereof, since the condensation reaction between the thiourea compound and the substituted malonic ester is substantially independent of the substituents on the malonic ester, simply by substituting an appropriate malonic ester, such as allyl-(2-cyclohexenyl)- diethyl malonate, for the ethyl- (1-methylbutyl)-diethyl malonate employed in Examples I-III. It should also be understood that the N-methyl thiobarbituric acids, such as l-methyl-5-ethyl-5-(1'-methylbutyl)-thiobarbituric acid and 1 methyl 5 allyl5-(1-methylbutyl)-thiobarbituric acid, can be prepared by using the appropriate N-rnethyl substituted malonic ester.

It will be evident from the foregoing that the present invention provides a process which produces a highly puriiii . 7 s r l lied thiobarbituricacid with only one precipitation of the barbituric acid from the condensation reaction mixture, whereas previously it was necessary to dissolve the crude salt in cold water and precipitate with a mineral acid, such as hydrochloric acid and thereafter further purifyingthe crude acid by dissolving the first precipitate in dilute aqueous alkali and reprecipitating with a dilute. acid-or carbon dioxide and recrystallization. It will be evident'that by eliminating the several reprecipitation steps necessary to obtain a product having the desired purity, the present process produces a higher yield of a highly purified product in a shorteroverall elapsed proces sing time which thereby results in a much more economical method of manufacturing thiobarbituric acids.

Others may readily adapt the invention for use under various conditions of service, by employing one or more of the novel features disclosed or equivalents thereof. As at present advised with respect to the apparent scope of my invention, I desire to claim the following subject matter.

1. A process of preparing a barbituric acid having the general formula:

wherein R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkylene, cyclohexenyl, and phenyl groups, R is selected from the group consisting of hydrogen and a lower alkyl and S is sulfur which comprises, condensing a iii-substituted malonic ester having the general formula:

COOR" COOR" wherein R and R have the above designated values and R is a lower alkyl group with a metallo derivative of a compound selected from the group consisting of thiourea, and N-lower alkyl thiourea, said condensation being carried out at a temperature of between 35 and 60 C. at atmospheric pressure which precludes decomposition of the said barbituric acid, and recovering the free acid in a highly purified form without requiring recrystallization from an organic solvent solution.

2. A process according to claim 1 characterized by the said metallo derivative being an alkali metal derivative which is formed by reacting the said urea compound with a compound selected from the group consisting of an alkali metal alcoholate, an alkali metal hydride, an alkali metal cyanamide, and an alkali metal amide.

3. A process according to claim 1 characterized by carrying out the said condensation reaction in the presence of an alkali metal alcoholate and an excess of the said urea compound.

4. A process according to claim 3 characterized by removing from the said condensation reaction mixture the alcohol formed during the said condensation reaction.

5. A process according to claim 1 characterized by condensing a di-substituted malonic ester with a thiourea in g the presence of an alkali metal alcoholate reagent at a temperature of about C.

6. A process according to claim 5 characterized by employing sodium methylate in methanol as the alkali metal alcoholate reagent.

7. A processs according to claim 6 characterized by removing from the said condensation reaction mixture the methanol formed during the said condensation reaction.

8. A process according to claim 1 characterized by acidifying the reaction mixture which has been diluted vgithat lqastan eqnal volume of water by the ad ditiqn o f Q'fAlpr p'c'qsg according t6 c1aim 8 chai actcrizcd by acidifying the said dilnteaq cqus reaction mixture with acetic acid. I

"10, A ptqce ss according to claim 1 characte izedby condensing .d icthyl ethyl-(l-methylbutyl) malonate with Hhiouwa- V 11 ,A, pro c e 'ss accqrding to claim 1 characterized by cpmicnsi'nQ dicthyl 'ailyl-(l-mcthylb utyl) malonate with 'mi ia J "12;. A pr oc e ssta ccq dingto ciairn 1 characte ized by QQQIAQPKdkFhY hY ma at i h l i u 13. A p occ ss accoi dingtb claim ,lchagactggiggi by a thic'iii'rea.

14. A process according t9 claim 1 charactegizcgi by.

References Cited intha file of.-this patent UNLTED STATES PATENTS Van Heyningcn Dgc. 9, 1152 OTHER REFERENCES Dcx e t a1.: I. Am. Chem. S9c vo1. 43 677-68 5 (1921 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,876,225 March 3, 959

George H. Donnison s in the-printed specification It is hereby certified that error appear tion and that the said Letters of the above "numbered patent requiring correc Patent should read as corrected below.

Column 6, line 31, after "lower alkylene," insert cyclohexyl,

Signed and sealed this 14th day of July 1959.

(SEAL) Attest:

KARL H, AXLINE Attesting Oflicer ROBERT C. WATSON Commissioner of Patents 

1. A PROCESS OF PREPARING A BARBITURIC ACID HAVING THE GENERAL FORMULA: 